Several methods are known for the preparation of cetirizine of the formula I. According to European Patent Application No. 58,146 (Chem. Abstr., 98, 34599r), an ester or an amide of the formula wherein Y stands for a group of the formula —OR1 or an amino group, wherein R1 means an alkyl group, is hydrolized to obtain the compound of the formula I.
Starting from the methyl ester of the formula V, after hydrolysis with potassium hydroxide, the potassium salt of cetirizine is obtained in a yield of 59%. From the potassium salt the corresponding acid is formed in a yield of 81%, and the desired dihydrochloride of cetirizine is obtained in a yield of 80%. Thus, the total yield of the known process amounts to 38.2%. A rather great drawback of the known process consists in the fact that the esters of the formula V used as the starting compound can be prepared only with difficulties and in a poor yield. Thus, the 1-[(4-chloro-phenyl)phenylmethyl]piperazine of the formula is reacted with methyl 2-chloroethoxyacetate of the formula to obtain the corresponding methyl ester of the formula V—after chromatography—in a yield of as low as 10.6%.
In the European Patent Application referred to above the possibility is mentioned that cetirizine can be prepared also from the acetic amide of the formula V, wherein Y stands for an amino group, by hydrolysis. However, neither any Example, nor yield data are given for the hydrolysis of the acetic amide of the formula V. According to a later communication (Synthesis, 1995, 766), the acetamide of the formula V is hydrolized in hydrochloric acid at 50° C. to obtain cetirizine in a yield of 71%.
Even three methods are known for the preparation of the acetamide of the formula V. For example, the 1-[(4-chloro-phenyl)phenylmethyl]-piperazine of the formula VI is reacted with 2-chloroethoxy-acetamide of the formula in the presence of an acid binding agent to obtain the acetamide of the formula V in a yield of 47%. According to a second method, the {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol of the formula is converted to the sodium salt with sodium hydride, and the salt is reacted with a chloroacetamide of the formula wherein X represents a chloro atom, R1 and R2 stand for a hydrogen atom. However, the yield of the reaction is merely 11%. According to the third method, the acetamide of the formula V can be also prepared from the corresponding methyl ester of the formula V, wherein Y means a methoxy group, by reaction with ammonia in a yield of 54%. Taking into consideration the low yield (27.8%) of the preparation of the methyl ester, the total yield is as low as 15.0%. Consequently, the latter known synthesis of cetirizine is uneconomical, too.
The process of UK-P No. 2 225 320 (Chem. Abstr., 113, 191395s) aims at the elimination of the disadvantages of the above known processes by preparing cetirizine from the {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol of the formula III which is converted to the potassium salt with potassium tert-butylate. The potassium salt is reacted with sodium chloro-acetate to obtain cetirizine dihydrochloride in a yield of 48.8%. In addition, 5.1% of a second generation product are obtained. Also an improved process is described for the preparation of the {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol of the formula III according to which 1-[(4-chlorophenyl)phenyl-methyl]piperazine of the formula VI is reacted with ethylene chlorohydrine in a yield of 90.4%, the total yield of the synthesis, referred to the piperazine derivative of the formula VI, is merely 48.7%.
The latter known process has a further drawback. The reaction of the ethanol derivative of the formula III with sodium chloro-acetate can be carried out in a relatively acceptable yield if the reactants are added in several portions to the solution of the ethanol derivative of the formula III. The addition of the reactants is to be programmed on the basis of a continuous monitoring of the composition of the reaction mixture. This technology is rather awkward, especially on industrial scale.
The latter known process is tried to be improved by the method described in PL-P No. 163 415 (Chem. Abstr., 123, 55923s) according to which the reaction is performed in a system consisting of two phases, in the presence of an indifferent organic solvent and aqueous sodium hydroxide solution to obtain cetirizine dihydrochloride in a yield of 60%. Although this method is less complicated than the one known from UK-P No. 2 225 320, the total yield amounts to only 54% as calculated for the ethanol derivative of the formula III that can be prepared in the most favourable way.
A further method for the preparation of cetirizine is known from UK-P No. 2 225 321 (Chem. Abstr., 113, 191396t) according to which the the 1-[(4-chloro-phenyl)phenylmethyl]-piperazine of the formula VI is reacted with chloroethoxyacetonitrile to obtain the nitrile derivative of the formula that is hydrolized in acidic or alkaline medium to cetirizin. In this way, cetirizin dihydrochloride is obtained from the nitrile derivative of the formula IX in a total yield of 60.5% in case of the acidic hydrolysis, and in a total yield of 65.6% in case of the alkaline hydrolysis.
However, the reaction of 1-[(4-chlorophenyl)phenylmethyl]-piperazine of the formula VI with chloroethoxyacetonitrile produces the nitrile derivative in a yield of 86.4% thereby reducing the total yield of the synthesis to 52.2% and 56.6%, respectively.
It should be also taken into consideration that, according to the literature [E. J. Salmi, R. Leimu and H. Kallio, Suomen Kemistilehti, 17B, 17-19 (1944)], chloroethoxy-acetonitrile can be prepared from ethylene chlorohydrin in two steps using the very poisonous copper(l) cyanide in a total yield of 58%.
Finally, a simple method of preparation is aimed by the process known from published European Patent Application No. 801,064 according to which cetirizine is prepared from 1-[(4-chlorophenyl)phenylmethyl]-piperazine of the formula VI with 2-chloroethoxyacetic acid in an indifferent solvent in the presence of an acid binding agent. The publication has only one example that does not contain either yield or quality data for the product. Furthermore, a great drawback of this method consists in the unavailability of 2-chloroethoxyacetic acid on an industrial scale.
The aim of the invention is to provide an economical process for the preparation of cetirizine that satisfies the most severe quality requirements.